Pemphigus is an autoimmune blistering disease of the skin and mucous membranes characterized by antibodies against the keratinocyte cell surface adhesion proteins desmoglein (Dsg) 1 and 3 (Stanley, 2003 Pemphugus. In: Fitzpatrick's dermatology in general medicine, New York: McGraw-Hill, 558-67). There are two primary forms of pemphigus, pemphigus foliaceus (PF) and pemphigus vulgaris (PV) to PF is characterized by autoantibodies against Dsg1, which cause blistering of the skin, but not mucous membranes, due to loss of cell adhesion in the superficial epidermis. Mucosal PV is characterized by autoantibodies against Dsg3, which cause suprabasilar blistering of the mucous membranes. Mucocutaneous PV patients, who demonstrate both mucous membrane and skin involvement, usually develop additional autoantibodies against Dsg1. In both PV and PF, anti-Dsg antibodies are responsible for the positive direct and indirect immunofluorescence tests that are the pathognomonic feature of these diseases.
Experiments using passive transfer of autoantibodies to neonatal mice have demonstrated that the anti-Dsg antibodies in patients' sera are pathogenic. However, not all anti-Dsg antibodies cause disease. Epitope mapping studies have shown that the more pathogenic autoantibodies tend to bind the amino-terminal extracellular domain of Dsgs that is predicted to form the trans-adhesive interface between cells, while the less or non-pathogenic antibodies bind more membrane-proximal extracellular domains.
Before the advent of corticosteroids, PV was a uniformly fatal disease due to severe blistering of the skin and oropharynx, with resulting malnutrition and sepsis. Currently, therapy for pemphigus relies on general immunosuppression, typically with corticosteroids, steroid-sparing agents, and/or adjunctive treatments such as intravenous immunoglobulin or plasmapheresis, most of which target the total antibody pool. Although mortality from pemphigus has decreased due to these therapies, a significant amount of patient morbidity and rarely mortality now results from side effects of these treatments. Therefore, there has been a long felt need in the field for more specific antibody-targeted therapies for pemphigus that would suppress or eliminate only the anti-Dsg autoantibodies. The present invention satisfies this need.